The therapeutic value of A-ring aromatic steroids such as estrone and estradiol are well known. In addition to the steroids itself, also derivatives of such steroids have been found to have therapeutic value. In this respect especially the 2-alkoxy-derivates of estrone and estradiol, such as 2-methoxy-3,17β-estradiol, need to be mentioned.
2-methoxy-3,17β-estradiol, also called 1,3,5(10)-estratrien-2,3,17β-triol-2-methyl-ether is an endogenous metabolite of estradiol. 2-methoxy-3,17β-estradiol has low estrogenic activity, but has been found to have important other biological effects, such as anti-cancer activity, as described herein below.
U.S. Pat. No. 5,504,074, U.S. Pat. No. 5,66,143 and U.S. Pat. No. 5,892,069 describe methods of treating mammalian diseases characterized by abnormal cell mitosis using 2-methoxy-3,17β-estradiol. In addition WO-A-02/42319 describes 2-methoxy-3,17β-estradiol for the treatment of disease states characterized by abnormal angiogenesis.
Undesirable cell mitosis is characteristic of many diseases, including, but not limited to, cancer, atherosclerosis, proliferation of solid tumours, vascular malfunctions, endometriosis, retinopathies, arthropathies, and abnormal wound healing. In addition, cell mitosis is important in a wide variety of biological functions, including but not limited to the normal development of the embryon, formation of the corpus luteum, cyclic proliferation of uterine endometrium, wound healing and inflammatory and immune responses.
U.S. Pat. No. 5,521,168 describes the use of 2-methoxy-3,17β-estradiol for lowering intraocular pressure. 2-methoxy-3,17β-estradiol also inhibits estrogen-induced pituitary tumour angiogenesis and suppresses tumour growth in Fisher 344 rats as reported by Banerjee, S. K. et al., Proc. Amer. Assoc. Cancer Res. 39, March 1998.
Processes for the preparation of 2-methoxy-3,17β-estradiol are known in the art. The article titled “Synthesis of 2-methoxyestrogens” by J. Fishman, published in the J. Am. Chem. Soc., 5 Mar. 1958, pages 1213-1216, describes the preparation of 2-methoxy-estradiol starting from estradiol. The first step of the described process comprises an etherification of estradiol with 2-chloro-5-nitrobenzophenone to its nitrobenzophenone ether. The described procedure for this step is, however, very cumbersome and results in a relatively low yield of about 45% m/m per turnover on starting compound estradiol. The etherification of estradiol with 2-chloro-5-nitrobenzophenone was carried out in an ethanolic potassium hydroxide solution. After refluxing for 48 hours the solution was concentrated to half the volume and poured into a sodium hydroxide solution. Hereafter the suspension was extracted 3 times with chloroform and after drying a yellow viscous oil was obtained. The oil was dissolved in a 1:1 petroleum ether-benzene mixture and chromatographed on alumina. Elution with benzene gave an oil which on trituration with ether crystallized as the estradiol nitrobenzophenone ether.
In subsequent steps the estradiol nitrobenzophenone ether is acetylated, followed by oxidation and methylation to give 2-methoxy-17β-acetoxy-Δ1,3,5 (10)-estratriene 3-(2-Benzoyl-4-nitro)-phenyl ether. From this last compound 2-methoxy-3,17β-estradiol can be prepared by either hot alkaline hydrolysis or by piperidine cleavage followed by hydrolysis with ethanolic potassium hydroxide.
A disadvantage of this process is the fact that the first step is very time-consuming and can take up to 60 hours. Such a time-consuming process step is especially unattractive when the process is to be applied at an industrial scale. Moreover, the first step results in a relatively poor yield of only 45% m/m.
Advantageously, a process has now been found which allows the first step to be carried out at an industrial scale within an economically attractive timeframe. With the process according to the invention the first step can be carried out within less than about 20 hours and, if desirable, even within less than 10 hours. In addition higher yields can be obtained.